Nivolumab for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers

PD-1 Immune Checkpoint Inhibition for the Reversal of Squamous Dysplasia in High Risk Current and Former Smokers With or Without a History of Lung Cancer

The goal of this clinical research study is to determine whether the PD-1 inhibitor (Programmed cell death protein 1) nivolumab improves premalignant bronchial dysplastic lesions in subjects that are at high risk for the development of lung cancer, including those with a prior smoking history, or history of lung cancer or head and neck cancer. The safety and tolerability of nivolumab will also be studied.

Study Overview

• Status: Recruiting
• Conditions: Tobacco Smoking; Bronchial Dysplasia; History of Non-Small Cell Lung Cancer; History of Head and Neck Cancer
• Intervention / Treatment: Drug: Nivolumab

Detailed Description

This is a single-institution, open-label, single-arm, two-stage, phase II study of the PD-1 inhibitor nivolumab in patients at high risk for lung cancer. Simon's two-stage design will be used. In the first stage, 18 subjects will be enrolled. If at least 7 subjects respond to nivolumab, then an additional 24 subjects will be enrolled for a total of 42 subjects. The central hypothesis to be tested by this trial is that immune evasion contributes to malignant transformation of premalignant bronchial dysplastic lesions into invasive lung cancers, and that blocking PD-1 will allow the immune system to target and eradicate premalignant bronchial dysplastic lesions, thereby preventing the development of lung cancer.

Nivolumab 240 mg IV will be administered every two weeks for a total of four doses (8 weeks). Participants will undergo bronchoscopy with endobronchial biopsy at study entry, 2 months, and 6 months. The primary endpoint will be change in bronchial dysplasia between study entry and the 6 month timepoint. Secondary endpoints include safety and tolerability of nivolumab in patients with bronchial dysplastic lesions, and additional endobronchial histology endpoints. Exploratory endpoints will be used to identify predictive markers of response to nivolumab.

• Study Type: Interventional
• Enrollment (Estimated): 42
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Brandi Kubala; Phone Number: 303-724-1657; Email: brandi.kubala@cuanschutz.edu

Study Locations

• United States
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Recruiting
      • University of Colorado Anschutz Medical Campus
      • Contact: Brandi Kubala; Phone Number: 303-724-1657; Email: brandi.kubala@cuanschutz.edu
      • Sub-Investigator: Robert Keith, M.D.
    • Denver, Colorado, United States, 80220
      • Recruiting
      • Denver VA Hospital
      • Contact: Brandi Kubala; Phone Number: 303-724-1657; Email: brandi.kubala@cuanschutz.edu
      • Principal Investigator: Robert Keith, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

In order to be eligible to participate in this study, an individual must meet all of the following criteria:

1. Provision of signed and dated informed consent form
2. Stated willingness to comply with all study procedures and availability for the duration of the study
3. Male or female, aged > 18 years
4. A current or ex-smoker with a > 30 pack-year history of smoking and mild or worse sputum cytologic atypia or known bronchial dysplasia, OR history of non-small cell lung cancer (stage I, II, or IIIA) with > 10 pack-year history of smoking and no evidence of active disease at least 1 year after definitive treatment, OR history of head and neck cancer (stage I, II, III, or IVA) with > 10 pack-year history of smoking and no evidence of active disease at least 1 year after definitive treatment. An ex-smoker is defined as no tobacco use in the prior 12 months
5. Endobronchial dysplasia (score > 4) on screening bronchoscopy
6. Total granulocyte count > 1500
7. Platelet count > 100,000
8. Serum creatinine < 1.5 mg/dL
9. Total bilirubin < 2.0 mg/dL
10. Transaminases and alkaline phosphatase < 2.5x upper limit of normal
11. Albumin > 2.5 mg/dL
12. ECOG performance status ≤ 1
13. Participants must be able and willing to undergo three bronchoscopies: before, after four doses of nivolumab (8 weeks), and after 6 months

Exclusion Criteria:

An individual who meets any of the following criteria will be excluded from participation in this study:

1. Participants may not be currently receiving immune checkpoint inhibitor treatment or have been treated with immune checkpoint inhibitors in the past (including anti-programmed cell death receptor [PD]-1, anti-programmed death ligand 1 [PD-L1], and anti-cytotoxic T-lymphocyte associated protein 4 [CTLA4] monoclonal antibodies)
2. Patients cannot receive any other investigational anti-cancer agents while participating in the study
3. Participants cannot have used any other investigational agents within the previous six months
4. History of allergic reactions attributed to compounds of similar chemical or biologic composition to nivolumab
5. Clinically apparent bleeding diathesis (i.e., bleeding that is spontaneous, excessive, or delayed in onset following tissue injury results from a localized pathologic process or a disorder of the hemostatic process, involving a complex interplay among vascular integrity, platelet number and function, coagulation factors, and fibrinolysis)
6. Cardiac dysrhythmia that is potentially life-threatening, such as ventricular tachycardia, multifocal premature ventricular contractions or supraventricular tachycardias with a rapid ventricular response. Well-controlled atrial fibrillation or rare (< 2 minute) premature ventricular contractions are not exclusionary
7. History of coronary artery disease, including myocardial infarction, congestive heart failure (LV ejection fraction <50% or clinically significant diastolic dysfunction), or any serious medical condition which would preclude a patient from undergoing a bronchoscopy or would jeopardize the goals of the study
8. Individuals who are HIV-positive will be considered on a case-by-case basis, but will be required to meet criteria related to patient safety and data integrity, as assessed by the study investigators
9. History of hepatitis B or hepatitis C infection that is untreated and/or with a detectable viral load
10. Hypoxemia (less than 90% saturation with supplemental oxygen)
11. Severe obstructive lung disease (GOLD Stage III or IV, FEV1<30% predicted)
12. Prior chemotherapy or thoracic radiation within the past 1 year
13. Participants with findings on CT chest suspicious for lung cancer (Lung-RADS category 4) will not be allowed to enroll until they have undergone additional evaluation for malignancy and an alternative (i.e., non-malignant) diagnosis has been established
14. Current malignancy, with the exception of non-melanoma (i.e., basal cell or squamous cell) skin cancer. Patients with lung carcinoma in situ found during the study biopsy are also excluded.
15. History of a malignancy except for adequately treated non-melanoma (i.e., basal cell or squamous cell) skin cancer or in situ cervical cancer for which the subject has not been disease-free for 5 years. Patients with a history of non-small cell lung cancer (stage I, II, or IIIA) or head and neck cancer (stage I, II, III, or IVA) must have no evidence of active disease at least 1 year after definitive treatment.
16. History of stage IIIA NSCLC for which the only treatment was chemoradiation without surgery
17. Known or suspected autoimmune disease; subjects with type I diabetes mellitus, hypothyroidism requiring hormone replacement, or skin disorders not requiring systemic treatment are permitted to enroll
18. Conditions requiring systemic corticosteroids equivalent to > 10 mg prednisone per day or other immunosuppressive medications within 2 weeks of enrollment
19. Known interstitial lung disease that is symptomatic or may interfere with the detection or management of suspected drug-related pulmonary toxicity
20. History of interstitial pneumonitis requiring treatment with systemic corticosteroids or other immunosuppressive agents (e.g., mycophenolate, azathioprine)
21. Life expectancy of < 1 year
22. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 4 weeks prior to the start of nivolumab
23. Women must not be breastfeeding
24. Inability to give informed consent
25. Pneumonia or acute bronchitis for at least 2 weeks prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Nivolumab Injection [Opdivo]; 240 mg IV every 2 weeks for 4 doses	Drug: Nivolumab; Nivolumab is a human monoclonal antibody that blocks the interaction between PD-1 and its ligands, PD-L1 and PD-L2.; Other Names: BMS-936558; ONO-4538; Opdivo; MDX1106

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement in endobronchial histology	The primary endpoint is the dichotomous endpoint of whether a subject responds to PD-1 immune checkpoint inhibition using nivolumab. Response will be based on the 6-month change (difference between 6-month score and baseline score) in worst (i.e., maximum) histologic classification score, using the 2004 World Health Organization (WHO) classification scale for pre-invasive squamous lesions of the bronchus. The histologic classification consists of: normal (grade 1.0), reserve cell hyperplasia (grade 2.0), squamous metaplasia (grade 3.0), mild dysplasia (grade 4.0), moderate dysplasia (grade 5.0), severe dysplasia (grade 6.0), carcinoma in situ (grade 7.0) and invasive cancer (grade 8.0).	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of immune-related adverse events (irAEs)	Patients will be evaluated every 2 weeks to determine whether they have any immune-related adverse events (irAEs) using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE). In particular, patients will be monitored closely for evidence of dermatological, gastrointestinal, endocrine, renal, and pulmonary irAEs. Complete blood count, comprehensive metabolic profile, and thyroid function tests will be obtained at baseline and every 3 months for 1 year. A comprehensive metabolic profile will also be checked every 2 weeks. Subjects will be followed for a total of 1 year to monitor for development of irAEs after discontinuation of the study drug.	Every 2 weeks through 3 months, then every 3 months through 1 year
Additional endobronchial histology endpoints using the 2004 WHO classification scale for pre-invasive squamous lesions of the bronchus	Two-month change (difference between 2-month score and baseline score) in worst (i.e., maximum) histologic classification score; Using all dysplastic (i.e., histology score ≥ 4.0) baseline biopsy pairs, the change in average histology and dysplasia index; Using all matched biopsies, the change in worst histology, average histology, and dysplasia index; Using all matched biopsies from reference sites, the change in worst histology, average histology, and dysplasia index; Response to treatment of completers, based on worst histology	2 months and 6 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of T lymphocytes in bronchial dysplastic lesions that express PD-1	The proportion of T lymphocytes that express programmed death receptor 1 (PD-1) in pre- and post-treatment biopsies will be compared by immunofluorescence staining of formalin-fixed, paraffin-embedded tissue sections	Baseline, 2 months, and 6 months
Proportion of macrophages in bronchial dysplastic lesions that express PD-L1	The proportion of macrophages that express programmed death ligand 1 (PD-L1) in pre- and post-treatment biopsies will be compared by immunofluorescence staining of formalin-fixed, paraffin-embedded tissue sections	Baseline, 2 months, and 6 months
Quantification of CD4+ T lymphocyte subsets in bronchial dysplastic lesions	Pre- and post-treatment biopsies will be stained by immunofluorescence for Th1, Th2, and Treg CD4+ T lymphocytes	Baseline, 2 months, and 6 months
Ratio of M1:M2 macrophages in bronchial dysplastic lesions	Pre- and post-treatment biopsies will be stained by immunofluorescence for CD68, HLA-DRA, and CD206. The ratio of M1 (CD68/HLA-DRA) to M2 (CD68/CD206) macrophages will be determined.	Baseline, 2 months, and 6 months
Number of non-synonymous mutations in bronchial dysplastic lesions	The number of non-synonymous mutations in bronchial dysplastic lesions will be determined by whole exsome sequencing	Baseline

Collaborators and Investigators

• Sponsor: University of Colorado, Denver
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Robert Keith, MD, University of Colorado, Denver

Study record dates

Study Major Dates

• Study Start (Actual): January 30, 2019
• Primary Completion (Estimated): December 1, 2025
• Study Completion (Estimated): December 1, 2026

Study Registration Dates

• First Submitted: October 24, 2017
• First Submitted That Met QC Criteria: November 15, 2017
• First Posted (Actual): November 20, 2017

Study Record Updates

• Last Update Posted (Actual): March 21, 2024
• Last Update Submitted That Met QC Criteria: March 19, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Keywords: Nivolumab; PD-1; Precancerous Conditions; Lung Cancer Immunoprevention
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms; Lung Diseases; Neoplasms by Site; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Immunological; Immune Checkpoint Inhibitors; Nivolumab
• Other Study ID Numbers: 17-1492.cc

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No